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US20070060582A1 - 1,4-Disubstituted isoquinilone derivatives as raf-kinase inhibitors useful for the treatment of proliferative diseases - Google Patents

1,4-Disubstituted isoquinilone derivatives as raf-kinase inhibitors useful for the treatment of proliferative diseases Download PDF

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US20070060582A1
US20070060582A1 US10/573,208 US57320804A US2007060582A1 US 20070060582 A1 US20070060582 A1 US 20070060582A1 US 57320804 A US57320804 A US 57320804A US 2007060582 A1 US2007060582 A1 US 2007060582A1
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phenyl
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Cynthia Fink
Lawrence Perez
Timothy Ramsey
Naeem Yusuff
Richard Versace
David Batt
Michael Sabio
Sunkyu Kim
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to the discovery of novel compounds that inhibit B-RAF kinase, a serine/threonine kinase that functions in the MAP kinase signaling pathway, and to the use of the compounds for the treatment of diseases characterized by an aberrant MAP kinase signaling pathway, e.g., proliferative diseases like certain cancers.
  • MAP kinase signaling pathway Many growth factors send their signal to proliferate from the extracellular environment to the cell nucleus via the MAP kinase signaling pathway.
  • the growth factors activate transmembrane receptors located on the cell surface which in turn start a cascade whereby RAS is activated and recruits RAF kinase to the membrane where it is activated and in turn activates MEK kinase which then activates ERK kinase.
  • Activated ERK kinase can move to the nucleus where it activates various gene transcription factors. Aberrations in this pathway can lead to altered gene transcription, cellular growth and contribute to tumorogenicity by negatively regulating apoptosis and transmitting proliferative and angiogenic signals.
  • Inhibitors of RAF kinase have been shown to block signaling through the MAP kinase signaling pathway in cell culture.
  • the RAF kinase family is known to have three members designated C-RAF, also known as RAF-1, B-RAF and A-RAF. It has been reported that B-RAF kinase is commonly activated by one of several somatic point mutations in human cancer, including 59% of the melanoma cell lines tested. See Davies et al., Nature , Vol. 417, pp. 949-954 (2002).
  • the compounds described herein are efficient inhibitors of RAF kinase, particularly C-RAF kinase and wild and mutated B-RAF kinase, particularly the V599E mutant B-RAF kinase.
  • the RAF kinase inhibiting property of the inventive compounds makes them useful as therapeutic agents for the treatment for proliferative diseases characterized by an aberrant MAP kinase signaling pathway, particularly melanoma and other cancer having mutated B-RAF, especially wherein the mutated B-RAF is the V599E mutant.
  • the present invention also provides a method of treating other conditions characterized by mutant B-RAF, e.g., benign Nevi moles having mutated B-RAF, with the isoquinoline compounds.
  • the present invention relates compounds of the formula (I) wherein
  • the compounds of formula (I) inhibit RAF kinase and have pharmaceutical utility based on this property.
  • lower denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being unbranched or branched one or more times.
  • the present compounds may be in the form of isomeric mixtures or in the form of pure isomers, preferably in the form of an enantiomerically pure diastereoisomer.
  • the index r is preferably 0 or 1. It may also be 2.
  • the index n is preferably 0 or 1, especially 0. It may also be 2.
  • the index m is preferably 0, 1 or 2, especially 0, or also 1.
  • J is heteroaryl containing at least one, but not more than three N.
  • Lower alkyl is especially C 1-4 alkyl, e.g., n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl or, especially, methyl or also ethyl, or, in the case of Y as lower alkyl, it may be especially isopentyl.
  • Lower alkyl is unsubstituted or substituted by hydroxy or halogen e.g. Br, Cl or F preferably F.
  • Aryl is preferably an aromatic radical having from 6-14 carbon atoms, especially phenyl, naphthyl, fluorenyl or phenanthrenyl, the mentioned radicals being unsubstituted or substituted by one or more substituents, preferably up to three, especially one or two substituents, especially selected from amino; mono- or di-substituted amino; halogen; alkyl; substituted alkyl; hydroxyl; etherified or esterified hydroxyl; nitro; cyano; carboxy; esterified carboxy; alkanoyl; carbamoyl; N-mono- or N,N-di-substituted carbamoyl; amidino; guanidine; mercapto; sulfo; phenylthio; phenyl-lower alkylthio; alkylphenylthio; phenylsulfinyl; phenyl-lower alkylsulfinyl; al
  • Heteroaryl is preferably an unsaturated heterocyclic radical in the bonding ring and is preferably mono- or also bi- or tri-cyclic; wherein at least in the ring bonding to the radical of the molecule of formula (I) one or more, preferably from 1-4, especially 1 or 2 carbon atoms of a corresponding aryl radical have been replaced by a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the bonding ring having preferably from 4-14, especially from 5-7 ring atoms; wherein heteroaryl is unsubstituted or substituted by one or more, especially from 1-3, identical or different substituents from the group consisting of the substituents mentioned above as substituents of aryl; and is especially a heteroaryl radical selected from the group consisting of imidazolyl, thienyl, furyl, pyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl,
  • Heteroaryl is especially a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, which heterocycle may be unsubstituted or substituted, especially by lower alkyl, such as methyl; preference is additionally given to a radical selected from 2-methyl-pyrimidin-4-yl, 1H-pyrazol-3-yl and 1-methyl-pyrazol-3-yl.
  • Heterocycloalkyl is especially a saturated 5- or 6-membered heterocycle having 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, which heterocycle may be unsubstituted or substituted, especially by lower alkyl, such as methyl; preference is given to a radical selected from oxazol-5-yl and 2-methyl-1,3-dioxolan-2-yl.
  • Mono- or di-substituted amino is especially amino that is substituted by one or two identical or different radicals from lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; phenyl-lower alkyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is unsubstituted or, especially, is substituted by one or more, preferably one or two, substituents selected from nitro and amino, or also from halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl and carbamoyl; and phenyl-lower alkoxycarbonyl wherein the phenyl radical is unsubstituted or, especially, is substituted by one or more, preferably one or two, substituents selected from
  • Halogen is especially fluorine, chlorine, bromine or iodine, more especially fluorine, chlorine or bromine, in particular fluorine and chlorine.
  • Alkyl has preferably up to a maximum of 12 carbon atoms and is especially lower alkyl, more especially methyl, or also ethyl, n-propyl, isopropyl or tert-butyl.
  • Substituted alkyl is alkyl as last defined, especially lower alkyl, preferably methyl, which may contain one or more, especially up to 3 substituents, selected especially from the group consisting of halogen, especially fluorine, and also amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, alkoxy, cyano, carboxy, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl. Trifluoromethyl is an important substituted alkyl.
  • Etherified hydroxy is especially C 8-20 alkyloxy, such as n-decyloxy; lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy or n-pentyloxy; phenyl-lower alkoxy, such as benzyloxy or also phenyloxy; or, alternatively or additionally to the preceding group, C 8-20 alkyloxy, such as n-decyloxy; halo-lower alkoxy, such as trifluoromethyloxy or 1,1,2,2-tetrafluoroethoxy.
  • Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy; or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
  • Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl or phenyloxycarbonyl.
  • Alkanoyl is especially alkyl-carbonyl, more especially lower alkanoyl, e.g., acetyl.
  • N-Mono- or N,N-di-substituted carbamoyl is especially substituted at the terminal nitrogen by one or two substituents lower alkyl, phenyl-lower alkyl or hydroxy-lower alkyl.
  • Alkylphenylthio is especially lower alkylphenylthio.
  • Alkylphenylsulfinyl is especially lower alkylphenylsulfinyl.
  • Alkylphenylsulfonyl is especially lower alkylphenylsulfonyl.
  • Pyridyl Y is preferably 3- or 4-pyridyl.
  • Unsubstituted or substituted cycloalkyl is preferably C 3-8 cycloalkyl, which is unsubstituted or is substituted in the same manner as aryl, especially as defined for phenyl.
  • Preference is given to cyclohexyl, or also cyclopentyl or cyclopropyl.
  • Preference is given also to 4-lower alkyl-cyclohexyl, such as 4-tert-butylcyclohexyl.
  • Aryl in the form of phenyl that is substituted by lower alkylenedioxy, such as methylenedioxy, bonded to two adjacent carbon atoms is preferably 3,4-methylenedioxyphenyl.
  • An N-oxide of a compound of formula (I) is preferably an N-oxide in which an isoquinoline ring nitrogen or a nitrogen in the J moiety carries an oxygen atom, or more than one of the mentioned nitrogen atoms carry an oxygen atom.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula (I), or an N-oxide thereof.
  • Such salts are formed, e.g., by compounds of formula (I), or an N-oxide thereof, having a basic nitrogen atom as acid addition salts, preferably with organic or inorganic acids, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, e.g., hydrohalic acids, such as hydrochloric acid (HCl); sulfuric acid; or phosphoric acid.
  • Suitable organic acids are, e.g., carboxylic phosphonic, sulfonic or sulfamic acids, e.g., acetic acid; propionic acid; octanoic acid; decanoic acid; dodecanoic acid; glycolic acid; lactic acid; 2-hydroxybutyric acid; gluconic acid; glucosemonocarboxylic acid; fumaric acid; succinic acid; adipic acid; pimelic acid; suberic acid; azelaic acid; malic acid; tartaric acid; citric acid; glucaric acid; galactaric acid; amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine, N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, maleic acid, hydroxymaleic acid,
  • salts with bases can also be formed, e.g., metal or ammonium salts, such as alkali metal; alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts; ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, e.g., triethylamine or tri(2-hydroxyethyl)amine; or heterocyclic bases, e.g., N-ethylpiperidine or N,N′-dimethyl-piperazine.
  • metal or ammonium salts such as alkali metal
  • alkaline earth metal salts e.g., sodium, potassium, magnesium or calcium salts
  • ammonium salts with ammonia or suitable organic amines such as tertiary monoamines, e.g., triethylamine or tri(2-hydroxyethyl)amine
  • heterocyclic bases e.g., N-ethylpiperidine or N,
  • a compound of formula (I), or an N-oxide thereof can also form internal salts.
  • any reference to the free compounds is also to be understood as including the corresponding salts, as appropriate and expedient.
  • J is aryl, preferably heteroaryl as defined above.
  • an important embodiment of the present invention relates to isoquinoline compounds of formula (Ia) wherein the variable substituents and preferences are the same as described above for the compounds of formula (I).
  • the ring members A, B, D and E are each CH or CQ and the ring member T is N.
  • An interesting embodiment of this invention are the compounds of formula (Ia), wherein the ring members A, B, E and T are each CH or CQ and D is N, or wherein the ring members A, B, D and T are each CH or CQ and E is N, or especially wherein the ring members B, D. E and T are each CH or CQ and A is N.
  • Another especially interesting embodiment of this invention are the compounds of formula (Ia), wherein the ring members A, B and D are each CH or CQ, and E and T are each N or wherein the ring members B. E and T are each CH or CQ and A and D are each N, or wherein the ring members A, D, and T are each CH or CQ and B and E are each N.
  • J is a bicyclic heteroaromatic ring system, such as indolyl, isoindolinyl, quinolyl, isoquinolyl, quinazolyl, purinyl, cinnolinyl, naphthyridinyl, phthalazinyl, isobenzofuranyl naphthyridinyl, phthalazinyl, chromenyl and purinyl.
  • a bicyclic heteroaromatic ring system may include Q as a substituent on either ring or on both rings of the bicyclic ring system, and on one or two carbon atoms on either or both rings of the bicyclic ring system.
  • inventive compounds inhibit RAF kinase and as such are useful for treating conditions and diseases characterized by an aberrant MAP kinase signaling pathway.
  • the present invention further relates to a method of treating a condition or disease characterized by an aberrant MAP kinase signaling pathway, which comprises administering to a patient an effective RAF kinase inhibiting amount of a compound of formula (I) wherein,
  • the patient is a mammal, generally a human, suffering from a disease that is characterized by an aberrant MAP kinase signaling pathway where aberrant is intended to mean that the signaling through the MAP kinase pathway is excessive relative to normal cells.
  • This can be measured by activation state specific antibodies to pathway members by methods, such as Western blot analysis or immunohistochemistry.
  • the disease characterized by an aberrant MAP kinase signaling pathway is a proliferative disease, particularly a cancer that expresses mutant B-RAF kinase or which overexpresses wild-type B- or C-RAF kinase.
  • Cancers wherein mutated B-RAF has been detected include melanoma, colorectal cancer, ovarian cancer, prostate, renal, gliomas, adenocarcinomas, sarcomas, breast cancer and liver cancer, preferably melanoma, colorectal cancer, ovarian cancer, gliomas, adenocarcinomas, sarcomas, breast cancer and liver cancer.
  • Mutations of B-RAF kinase are especially prevalent in melanomas.
  • a sample of diseased tissue is taken from the patient, for example, as a result of a biopsy or resection, and tested to determine whether the tissue produces mutant B-RAF kinase or overproduces wild-type B- or C-RAF kinase. If the test indicates that mutant B-RAF is produced or that wild-type B- or C-RAF kinase is overproduced in the diseased tissue, the patient is treated by administration of an effective RAF-inhibiting amount of an isoquinoline compound described herein. However, it is also possible to down-regulate the MAP kinase signaling pathway with a RAF kinase inhibiting compound if another kinase in the cascade is the cause of the aberration in the pathway.
  • B-RAF mutations are detected by allele specific PCR, DHPLC, mass spectroscopy and over-expression of wild-type B- or C-RAF detected by immunohistochemistry, immunofluoresense or Western blot analysis.
  • a particularly useful method of detecting B-RAF mutations is the polymerase chain reaction based method described in Example A. Similar methods are used to determine whether other kinases in the cascade are mutant or over-expressed.
  • a particularly important aspect of this invention relates to a method of treating melanoma, which comprises:
  • the B-RAF mutation is one of those described in the Davies et al. article cited above and listed in Table 1.
  • Table 1 TABLE 1 B-RAF Mutation Protein Change G1388A G463E G1388T G463V G1394C G465A G1394A G465E G1394T G465V G1403C G468A G1403A G468E G1753A E585K T1782G F594L G1783C G595R C1786G L596V T1787G L596R T1796A V599E TG1796-97AT V599D
  • the present invention particularly relates to a method of treating a disease characterized by mutant B-RAF kinase, which comprises detecting a mutation in the B-RAF kinase gene or protein in a tissue sample from a patient and treating the patient with an effective B-RAF kinase inhibiting compound, especially an isoquinoline compound described herein.
  • a important aspect of this invention includes those instances wherein the mutant B-RAF kinase exhibits a mutation described in Table 1, especially the V599E mutation.
  • a particularly important aspect of this invention includes those instances wherein disease is melanoma and the mutant B-RAF kinase exhibits a mutation described in Table, 1, especially the V599E mutation.
  • the RAF kinase inhibiting compounds utilized according to the inventive method include the compounds of formula (I), or N-oxides thereof, which have valuable pharmacological properties, as described above.
  • the invention provide the use of a compound of formula I as pharmaceutical.
  • the invention provides the use of a compound of formula I for the preparation of a medicament for the treatment of a disease characterized by an aberrant MAP kinase signaling pathway is a proliferative disease, particularly a cancer that expresses mutant B-RAF kinase or which overexpresses wild-type B- or C-RAF kinase.
  • a compound of formula (I), or an N-oxide thereof can be administered on its own or in combination with one or more other therapeutic agents, it being possible for fixed combinations to be used or for a compound according to the invention and one or more other therapeutic agents to be administered in a staggered manner over time or independently of one another, or the combined administration of fixed combinations and of one or more other therapeutic agents is possible.
  • the administration of a compound of formula (I), or an N-oxide thereof, for tumor treatment can be carried out, alongside or additionally, in combination with chemotherapy (combination with one or more other chemotherapeutic agents, especially cytostatics, or with hormones or compounds having a hormone-like activity), radiotherapy, immunotherapy, surgical treatment or combinations thereof.
  • therapeutic agents with which the compounds according to the invention can be combined especially one or more anti-proliferative, cytostatic or cytotoxic compounds, e.g., one or more chemotherapeutic agents selected from the group comprising an inhibitor of polyamine biosynthesis; an inhibitor of a different protein kinase, especially protein kinase C or of a tyrosine protein kinase, such as epidermal growth factor receptor protein tyrosine kinase; an inhibitor of a growth factor, such as vascular endothelial growth factor; a cytokine; a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor; hormones or hormone analogues; and a conventional cytostatic agent.
  • chemotherapeutic agents selected from the group comprising an inhibitor of polyamine biosynthesis; an inhibitor of a different protein kinase, especially protein kinase C or of a tyrosine protein kinase, such as epidermal
  • Compounds according to the invention are intended not only for the (prophylactic and, preferably, therapeutic) treatment of human beings, but also for the treatment of other warm-blooded animals, e.g., of commercially-useful animals, e.g., rodents, such as mice, rabbits or rats; or guinea pigs.
  • the invention relates also to the use of a compound of formula (I), or an N-oxide thereof, in inhibiting RAF kinase activity.
  • a compound of formula (I), or an N-oxide thereof can also be used for diagnostic purposes, e.g., in order that tumors obtained from warm-blooded animals, especially human beings, as the original “host” and transplanted into mice, can be examined for reduced growth after addition of such a compound, in order thus to study their sensitivity to the compound in question, thus allowing possible methods of treatment for a tumor disease in the original host to be ascertained and determined better.
  • r is from 0-2, preferably 1;
  • n 0 or 1
  • n 1 or, especially, 0;
  • A, B, D and E are each CH or CQ and T is N or
  • A, B, T and E are each CH or CQ and D is N or
  • A, B and D are each CH or CQ and E and T are each N;
  • Another interesting embodiment of the invention is a compound of formula (I) wherein
  • the compounds according to the invention can be prepared by processes known per se for other compounds, especially by:
  • a nucleofugal leaving group M is especially halogen, more especially bromine, iodine or, very especially, chlorine.
  • the reaction between the compound of formula II and the compound of formula (III) takes place in suitable inert polar solvents, especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially, ethanol or n-butanol; or it takes place in a melt without the addition of a solvent, especially when one of the reactants is in liquid form.
  • suitable inert polar solvents especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially, ethanol or n-butanol
  • the reaction takes place at elevated temperatures, preferably from approximately 60° C. to reflux temperature, e.g., under reflux conditions or at a temperature of from approximately 90° C. to approximately 110° C.
  • the compound of formula (III) can also be used in the form of a salt, e.g., in the form of an acid addition salt with a strong acid, such as a hydrogen halide, e.g., in the form of the hydrochloride salt; or the corresponding acid, e.g., HCl, can be added in a suitable solvent, e.g., an ether, such as dioxane.
  • a strong acid such as a hydrogen halide, e.g., in the form of the hydrochloride salt
  • a suitable solvent e.g., an ether, such as dioxane.
  • the reaction between the compound of formula (II) and the compound of formula (III) takes place in suitable, inert polar solvents, especially ethers, e.g., tetrahydrofuran (THF); or in a melt without the addition of a solvent, especially if one of the reaction partners is present in liquid form.
  • suitable, inert polar solvents especially ethers, e.g., tetrahydrofuran (THF); or in a melt without the addition of a solvent, especially if one of the reaction partners is present in liquid form.
  • the reaction takes place at elevated temperatures, preferably between about 80° C. and 140° C. in a pressure tube.
  • the compound of formula (III) can be used as a salt, e.g., as an basic addition salt with a strong base, such as potassium hydroxide or sodium hydride.
  • the protecting groups are groups which are customarily used in the synthesis of peptide compounds, but also in the synthesis of cephalosporins and penicillins, as well as of nucleic acid derivatives and sugars.
  • the protecting groups may already be present in the precursors and are to protect the functional groups in question against undesired secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis and the like.
  • the protecting groups for functional groups in starting materials whose reaction is to be avoided include especially those protecting groups (conventional protecting groups) which are customarily used in the synthesis of peptide compounds, cephalosporins, penicillins or nucleic acid derivatives and sugars.
  • the protecting groups may already be present in the precursors and are to protect the functional groups in question against undesired secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, etc. In some cases the protecting groups can cause the reactions to proceed selectively, e.g., stereoselectively.
  • protecting groups It is a characteristic of protecting groups that they can be removed easily, that is to say without undesired secondary reactions, e.g., by solvolysis, by reduction, by photolysis or enzymatically, e.g., also under conditions analogous to physiological conditions, and that they are not present in the end products.
  • the person skilled in the art will know or can readily find out which protecting groups are suitable in the reactions mentioned hereinbefore and hereinafter.
  • functional groups in the starting compounds that are not to take part in the reaction may be present in unprotected form or in protected form, e.g., protected by one or more of the protecting groups mentioned above under process a). All or some of the protecting groups are then removed by one of the methods mentioned under process a).
  • Salts of compounds of formula (I), or an N-oxide thereof, having a salt-forming group can be prepared in a manner known per se.
  • acid addition salts of compounds of formula (I) or their N-oxides can be obtained, e.g., by treatment with an acid or a suitable anion exchange reagent.
  • salts having two acid molecules e.g., a dihalide of a compound of formula (I), or of an N-oxide thereof
  • salts having one acid molecule per compound of formula (I), or N-oxide thereof e.g., into a monohalide
  • that can be achieved e.g., by heating to the molten state or, e.g., by heating in solid form under a high vacuum at elevated temperature, e.g., from 130-170° C., one molecule of the acid being expelled per molecule of a compound of formula (I), or of an N-oxide thereof.
  • Salts can be converted into the free compounds in customary manner, e.g., by treatment with a suitable basic agent, e.g., with alkali metal carbonates; hydrogen carbonates or hydroxides, e.g., potassium carbonate or sodium hydroxide.
  • a suitable basic agent e.g., with alkali metal carbonates; hydrogen carbonates or hydroxides, e.g., potassium carbonate or sodium hydroxide.
  • Stereoisomeric mixtures e.g., mixtures of diastereoisomers
  • diastereoisomeric mixtures can be separated into the individual diastereoisomers by fractional crystallization, chromatography, solvent partitioning and the like. The separation may be carried out either at the stage of one of the starting materials or in the case of the compounds of formula (I) themselves.
  • Enantiomers can be separated by formation of diastereoisomeric salts, e.g., by salt formation with an enantiomerically pure chiral acid, or by chromatographic methods, e.g., by chromatography, e.g., HPLC, on chromatographic carrier materials with chiral ligands.
  • a compound of formula (I) can be converted into a corresponding N-oxide.
  • the reaction is carried out with a suitable oxidizing agent, preferably a peroxide, e.g., m-chloroperbenzoic acid, in a suitable solvent, e.g., a halogenated hydrocarbon, such as chloroform or methylene chloride; or in a lower alkanecarboxylic acid, such as acetic acid, preferably at a temperature of from 0° C. to the boiling temperature of the reaction mixture, especially approximately room temperature.
  • a suitable oxidizing agent preferably a peroxide, e.g., m-chloroperbenzoic acid
  • a suitable solvent e.g., a halogenated hydrocarbon, such as chloroform or methylene chloride
  • a lower alkanecarboxylic acid such as acetic acid
  • a compound of formula (I), or an N-oxide thereof, wherein Z is amino substituted by one or two identical or different radicals selected from lower alkyl, hydroxy-lower alkyl and phenyl-lower alkyl can be converted into the compound that is correspondingly substituted at the amino group, e.g., by reaction with a lower alkyl halide, a hydroxy-lower alkyl halide, which is hydroxy-protected if necessary (see process a); or a phenyl-lower alkyl halide under reaction conditions analogous to those mentioned under process a).
  • epoxide e.g., ethylene oxide
  • polar solvents such as alcohols, e.g., methanol, ethanol, isopropanol or ethylene glycol
  • ethers such as dioxane
  • amides such as dimethyl formamide
  • phenols such as phenol
  • acid or basic catalysts e.g., of alkaline solutions, such as sodium hydroxide solution
  • hydrazine-doped solid phase catalysts such as aluminium oxide
  • in ethers e.g., diethyl ether
  • the reductive alkylation preferably takes place with hydrogenation in the presence of a catalyst, especially a noble metal catalyst, such as platinum or, especially, palladium, which is preferably bonded to a support material, such as carbon; or a heavy metal catalyst, such as Raney nickel, at normal pressure or at pressures of from 0.1-10 megapascals (MPa); or with reduction by means of complex hydrides, such as boron hydrides, especially alkali metal cyanoborohydrides, e.g., sodium cyanoborohydride, in the presence of a suitable acid, preferably of a relatively weak acid, such as a lower alkanecarboxylic acid or, especially, a sulfonic acid, such as p-toluenesulfonic acid; in customary solvents, e.g., alcohols, such as methanol or ethanol; or ethers, e.g., cyclic ethers, such as THF, in the absence or presence of water.
  • an amino group Z can be converted by acylation into an amino group that is substituted by lower alkanoyl, benzoyl, substituted benzoyl or by phenyl-lower alkoxycarbonyl wherein the phenyl radical is unsubstituted or substituted.
  • the corresponding acids contain a free carboxy group or are in the form of reactive acid derivatives thereof, e.g., in the form of the derived activated esters or reactive anhydrides, also reactive cyclic amides.
  • the reactive acid derivatives can also be formed in situ.
  • esters are especially esters that are unsaturated at the linking carbon atom of the radical to be esterified, e.g., of the vinyl ester type, such as vinyl esters, obtainable, e.g., by transesterification of a corresponding ester by vinyl acetate or activated vinyl ester method; carbamoyl esters obtainable, e.g., by treating the corresponding acid with an isoxazolium reagent, 1,2-oxazolium, or Woodward method; or 1-lower alkoxyvinyl esters obtainable, e.g., by treating the corresponding acid with a lower alkoxyacetylene, or ethoxyacetylene method; or esters of the amidino type, such as N,N-disubstituted amidino esters obtainable, e.g., by treating the corresponding acid with a suitable N,N′-disubstituted carbodiimide, e.g., N,N′-di
  • Anhydrides of acids may be symmetrical or, preferably, mixed anhydrides of those acids, e.g., anhydrides with inorganic acids, such as acid halides, especially acid chlorides obtainable, e.g., by treating the corresponding acid with thionyl chloride, phosphorus pentachloride, phosgene or oxalyl chloride, or acid chloride method; azides obtainable, e.g., from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid, or azide method; anhydrides with carbonic acid semiesters, e.g., carbonic acid lower alkyl semiesters, especially chloroformic acid methyl esters obtainable, e.g., by treating the corresponding acid with chloroformic acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-
  • Suitable cyclic amides are especially amides with 5-membered diazacycles of aromatic nature, such as amides with imidazoles, e.g., imidazole obtainable, e.g., by treating the corresponding acid with N,N′-carbonyldiimidazole, or imidazole method; or pyrazole, e.g., 3,5-dimethylpyrazole obtainable, e.g., via the acid hydrazide by treatment with acetylacetone, or pyrazolide method.
  • derivatives of carboxylic acids which are used as acylating agents, can also be formed in situ.
  • N,N′-disubstituted amidino esters can be formed in situ by reacting the mixture of the starting material of formula (I) and the acid used as acylating agent in the presence of a suitable N,N′-disubstituted carbodiimide, e.g., N,N′-dicyclohexylcarbodiimide or, especially, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.
  • a suitable N,N′-disubstituted carbodiimide e.g., N,N′-dicyclohexylcarbodiimide or, especially, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.
  • amino or amido esters of the acids used as acylating agent can be formed in the presence of the starting material of formula (I) to be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N′-disubstituted carbodiimide, e.g., N,N′-dicyclohexylcarbodiimide, and of an N-hydroxyamine or N-hydroxyamide, e.g., N-hydroxysuccinimide, optionally in the presence of a suitable base, e.g., 4-dimethylaminopyridine.
  • an N,N′-disubstituted carbodiimide e.g., N,N′-dicyclohexylcarbodiimide
  • an N-hydroxyamine or N-hydroxyamide e.g., N-hydroxysuccinimide
  • a suitable base e.g., 4-dimethylaminopyridine.
  • activation can be achieved in situ by reaction with N,N,N′,N′-tetraalkyluronium compounds, such as O-benztriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (in the absence or presence of 1,8-diazabicyclo[5.4.0]undec-7-ene-(1,5,5)) or O-(3,4-dihydro-4-oxo-1,2,3-benztriazolin-3-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.
  • N,N,N′,N′-tetraalkyluronium compounds such as O-benztriazol-1-yl-N,N,N′,N′
  • phosphoric acid anhydrides of the carboxylic acids can be prepared in situ by reacting an alkylphosphoric acid amide, such as hexamethylphosphoric acid triamide, in the presence of a sulfonic acid anhydride, such as 4-toluenesulfonic acid anhydride, with a salt, such as a tetrafluoroborate, e.g., sodium tetrafluoroborate, or with a different derivative of hexamethylphosphoric acid triamide, such as benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluoride, preferably in the presence of a racemization-reducing additive, such as N hydroxybenztriazole.
  • a sulfonic acid anhydride such as 4-toluenesulfonic acid anhydride
  • a salt such as a tetrafluoroborate, e.g., sodium tetrafluoroborate
  • an organic base is added, preferably a tertiary amine, e.g., a tri-lower alkylamine, especially ethyldiisopropylamine or, more especially, triethylamine, and/or a heterocyclic base, e.g., 4-dimethylaminopyridine or, preferably, N-methylmorpholine or pyridine.
  • a tertiary amine e.g., a tri-lower alkylamine, especially ethyldiisopropylamine or, more especially, triethylamine
  • a heterocyclic base e.g., 4-dimethylaminopyridine or, preferably, N-methylmorpholine or pyridine.
  • the condensation is preferably carried out in an inert, aprotic, preferably anhydrous solvent or solvent mixture, e.g., in a carboxylic acid amide, e.g., formamide or dimethylformamide; a halogenated hydrocarbon, e.g., methylene chloride, carbon tetrachloride or chlorobenzene; a ketone, e.g., acetone; a cyclic ether, e.g., THF or dioxane; an ester, e.g., ethyl acetate; or a nitrile, e.g., acetonitrile, or in a mixture thereof, where appropriate at reduced or elevated temperature, e.g., in a temperature range of from approximately ⁇ 40° C.
  • a carboxylic acid amide e.g., formamide or dimethylformamide
  • a halogenated hydrocarbon e.g., methylene chloride, carbon
  • arylsulfonyl esters are used also at approximately from +100-200° C., especially at temperatures of from 10-30° C., and, where appropriate, under an inert gas atmosphere, e.g., a nitrogen or argon atmosphere.
  • Aqueous, e.g., alcoholic; solvents, e.g., ethanol; or aromatic solvents, e.g., benzene or toluene, are also possible.
  • a nitro group Z in a compound of formula (I) can be reduced to an amino group, e.g., by reduction with metals or selective hydrogenation; e.g., by reaction with magnesium/ammonium sulfate in a water/alcohol mixture, such as methanol/water, at elevated temperature, e.g., from 30-60° C. (see Synth Commun , Vol. 25, No. 2, pp.
  • All the process steps mentioned in the present text can be carried out under reaction conditions which are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably those which are inert towards the reagents used and are solvents therefor, in the absence or presence of catalysts, condensing agents or neutralizing agents, e.g., ion exchangers, such as cation exchangers, e.g., in the H + form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from approximately ⁇ 100° C. to approximately 190° C., preferably from approximately ⁇ 80° C.
  • reaction conditions which are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably those which are inert towards the reagents used and are solvents therefor, in the absence or presence of catalysts, conden
  • salts can be present where salt-forming groups are present. Salts can also be present during the reaction of such compounds, provided that the reaction is not impaired thereby.
  • isomeric mixtures that form can be separated into the individual isomers, e.g., diastereoisomers or enantiomers, or into any desired mixtures of isomers, e.g., racemates or diastereoisomeric mixtures, e.g., analogously to the methods described under “Additional process steps”.
  • the solvents from which those that are suitable for a particular reaction can be selected include, e.g., water; esters, such as lower alkyl lower alkanoates, e.g., diethyl acetate; ethers, such as aliphatic ethers, e.g., diethyl ether or cyclic ethers, e.g., THF; liquid aromatic hydrocarbons, such as benzene or toluene; alcohols, such as methanol, ethanol or 1- or 2-propanol; nitriles, such as acetonitrile; halogenated hydrocarbons, such as methylene chloride; acid amides, such as dimethylformamide; basses, such as heterocyclic nitrogen bases, e.g., pyridine; carboxylic acids, such as lower alkanecarboxylic acids, e.g., acetic acid; carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, e.g
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage is used as starting material and the remaining steps are carried out, or the process is interrupted at any stage, or a starting material is formed under the reaction conditions or is used in the form of a reactive derivative or salt, or a compound obtainable by the process according to the invention is produced under the process conditions and is processed further in situ.
  • a starting material which lead to the compounds described above as being preferred, especially as being especially preferred, more especially preferred and/or very especially preferred.
  • the compounds of formula (I), or N-oxides thereof, including their salts can also be obtained in the form of hydrates, or their crystals can include, e.g., the solvent used for crystallization (presence in the form of solvates).
  • compositions which comprise a compound of formula (I), or an N-oxide thereof, as active ingredient and can be used especially in the treatment of the diseases mentioned at the beginning.
  • Special preference is given to compositions for enteral, such as nasal, buccal, rectal or, especially, oral and parenteral, such as intravenous, intramuscular or subcutaneous, administration to warm-blooded animals, especially human beings.
  • the compositions comprise the active ingredient on its own or, preferably, together with a pharmaceutically acceptable carrier.
  • the dose of active ingredient depends on the disease to be treated and on the species, its age, weight and individual condition, individual pharmacokinetic data and on the mode of administration.
  • the invention relates also to pharmaceutical compositions for use in a method of treating the human or animal body prophylactically or, especially, therapeutically, to a process for their preparation (especially in the form of compositions for the treatment of tumours) and to a method of treating the above-mentioned diseases, especially tumor diseases, more especially those mentioned above.
  • the invention relates also to processes, and to the use of compounds of formula (I), or an N-oxide thereof, for the preparation of pharmaceutical compositions comprising compounds of formula (I), or an N-oxide thereof, as active component (active ingredient).
  • a pharmaceutical composition which is suitable for administration to a warm-blooded animal, especially a human being or a commercially useful mammal, which is suffering from a disease characterized by an aberrant MAP kinase signaling pathway especially, a tumor disease, most particularly melanoma, comprising a compound of formula (I), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof where salt-forming groups are present, in an amount that is effective in inhibiting RAF kinase, particularly a mutant RAF kinase, together with at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the prophylactic or, especially, therapeutic treatment of tumor diseases and other proliferative diseases in a warm-blooded animal, especially a human being or a commercially useful mammal, which requires such treatment, especially which is suffering from such a disease comprising a novel compound of formula (I), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, as active ingredient in an amount that is effective prophylactically or, especially, therapeutically against the mentioned diseases.
  • compositions comprise from approximately 1% to approximately 95% active ingredient, dosage forms that are in single dose form preferably comprising from approximately 20% to approximately 90% active ingredient, and dosage forms that are not in single dose form preferably comprising from approximately 5% to approximately 20% active ingredient.
  • Unit dose forms are, e.g., dragées, tablets, ampoules, vials, suppositories or capsules.
  • Other dosage forms are, e.g., ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc.
  • capsules comprising from approximately 0.05 g to approximately 1.0 g of the active ingredient.
  • compositions of the present invention are prepared in a manner known per se, e.g., by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes.
  • Solutions of the active ingredient are preferably used, in addition also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, which, in the case of, e.g., lyophilized compositions which contain the active substance alone or together with a carrier, e.g., mannitol, can be prepared prior to use.
  • the pharmaceutical compositions may be sterilized and/or comprise excipients, e.g., preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, e.g., by means of conventional dissolving or lyophilizing processes.
  • the mentioned solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or solubilizers, e.g., Tween 80 [polyoxyethylene(20)sorbitan monooleate; trademark of ICI Americas, Inc., USA].
  • viscosity-increasing substances such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or solubilizers, e.g., Tween 80 [polyoxyethylene(20)sorbitan monooleate; trademark of ICI Americas, Inc., USA].
  • Suspensions in oil comprise as the oily component the vegetable, synthetic or semi-synthetic oils customary for injection purposes.
  • liquid fatty acid esters which comprise as the acid component a long-chained fatty acid having from 8-22 carbon atoms, especially from 12-22 carbon atoms, e.g., lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, e.g., oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, optionally with the addition of antioxidants, e.g., vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • antioxidants e.g., vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, e.g., mono-, di- or tri-hydric, alcohol, e.g., methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol and glycerol.
  • fatty acid esters which may be mentioned are, therefore ethyl oleate, isopropyl myristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethyleneglycerol trioleate from Gattefossé, Paris), “Labrafil M 1944 CS” (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and composed of glycerides and polyethylene glycol ester; Gattefossé, France), “Labrasol” (saturated polyglycolized glycerides prepared by alcoholysis of TCM and composed of glycerides and polyethylene glycol ester; Gattefossé, France) and/or “Miglyol 812” (triglyceride of saturated fatty acids having a chain length of from C 8-12 from Hüls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil
  • the preparation of the injection compositions is carried out in customary manner under sterile conditions, as are also the introduction thereof, e.g., into ampoules or vials and the sealing of the containers.
  • compositions for oral administration can be obtained, e.g., by combining the active ingredient with one or more solid carriers, granulating a resulting mixture, where appropriate, and processing the mixture or granules, if desired, where appropriate by addition of additional excipients, to tablets or dragée cores.
  • Suitable carriers are especially fillers, such as sugars, e.g., lactose, saccharose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g., tricalcium phosphate or calcium hydrogen phosphate; also binders, such as starches, e.g., corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch; cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, e.g., lactose, saccharose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates e.g., tricalcium phosphate or calcium hydrogen
  • Additional excipients are especially flow conditioners and lubricants, e.g., silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; or derivatives thereof.
  • flow conditioners and lubricants e.g., silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; or derivatives thereof.
  • Dragée cores can be provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorings or pigments may be added to the tablets or dragée coatings, e.g., for identification purposes or to indicate different doses of active ingredient.
  • suitable, optionally enteric, coatings there being used inter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • compositions for oral administration are also hard gelatin capsules and soft sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard gelatin capsules may contain the active ingredient in the form of granules, e.g., in admixture with fillers, such as corn starch; binders and/or glidants, such as talc or magnesium stearate; and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it likewise being possible to add stabilizers and detergents, e.g., of the polyoxyethylenesorbitan fatty acid ester type.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it likewise being possible to add stabilizers and detergents, e.g., of the polyoxyethylenesorbitan fatty acid ester type.
  • Suitable rectally administrable pharmaceutical compositions are, e.g., suppositories that consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, e.g., natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • aqueous solutions of an active ingredient in water-soluble form e.g., in the form of a water-soluble salt
  • aqueous injection suspensions that comprise viscosity-increasing substances, e.g., sodium carboxymethylcellulose, sorbitol and/or dextran; and, if desired, stabilizers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilisate and can be made into a solution prior to parenteral administration by the addition of suitable solvents.
  • Solutions used, e.g., for parenteral administration can also be used as infusion solutions.
  • Preferred preservatives are, e.g., antioxidants, such as ascorbic acid; or microbicides, such as sorbic acid or benzoic acid.
  • the invention relates especially to a process or a method for treating one of the pathological conditions that is characterized by an aberrant MAP kinase signaling pathway, especially a disease responsive to inhibition of RAF kinase, especially a corresponding tumour disease.
  • the compounds of formula (I), or an N-oxide thereof can be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount that is effective against the mentioned diseases, to a warm-blooded animal, e.g., a human being, requiring such treatment, the compounds being used especially in the form of pharmaceutical compositions.
  • a daily dose of from approximately 0.1 g to approximately 5 g, preferably from approximately 0.5 g to approximately 2 g, of a compound of the present invention is administered.
  • the starting materials used and the reaction conditions chosen are preferably such that the compounds mentioned as being preferred are obtained.
  • the starting materials of formulae (II) and (III) are known, can be prepared by processes known per se, or are available commercially; in particular, they can be prepared by processes analogous to those mentioned in the Examples.
  • any functional groups present that are not to take part in the reaction may be in protected form, if necessary. Preferred protecting groups, their introduction and their removal are described under process a) or in the Examples.
  • Step 1 involves reacting a compound of formula (IV) in a palladium mediated cross-coupling reaction of two suitable coupling partners, preferably under Negishi conditions.
  • the palladium-mediated coupling of a compound of formula (IV) is conducted in the presence of:
  • Step 2 involves the reaction of a compound of formula (II) with a compound of formula (III) wherein
  • the reaction between the compound of formula (II) and the compound of formula (III) takes place in suitable inert polar solvents, especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially, ethanol or n-butanol, or it takes place in a melt without the addition of a solvent, especially when one of the reactants is in liquid form.
  • suitable inert polar solvents especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially, ethanol or n-butanol
  • the reaction takes place at elevated temperatures, preferably from approximately 60° C. to reflux temperature, e.g., under reflux conditions or at a temperature of from approximately 60-110° C.
  • the compound of formula (III) can also be used in the form of a salt, e.g., in the form of an acid addition salt with a strong acid, such as a hydrogen halide, e.g., in the form of the hydrochloride salt; or the corresponding acid, e.g., HCl, can be added in a suitable solvent, e.g., an ether, such as dioxane.
  • a strong acid such as a hydrogen halide, e.g., in the form of the hydrochloride salt
  • a suitable solvent e.g., an ether, such as dioxane.
  • the reaction between the compound of formula (II) and the compound of formula (III) takes place in suitable, inert polar solvents, especially ethers, e.g., THF, or in a melt without the addition of a solvent, especially if one of the reaction partners is present in liquid form.
  • suitable, inert polar solvents especially ethers, e.g., THF
  • the reaction-takes place at elevated temperatures, preferably between about 80° C. and 140° C. in a pressure tube.
  • the compound of formula (III) can be used as a salt, e.g., as an basic addition salt with a strong base, such as potassium hydroxide or sodium hydride.
  • Step 1 involves the reaction of a compound of formula (V) with a compound of formula (III) wherein n, R, X and Y are as defined for a compound of formula (I), functional groups in the compounds of formulae (V) and (III) that are not to take part in the reaction being in protected form, if necessary, and removing any protecting groups that are present, wherein the starting compounds mentioned in process a) may also be in the form of salts where a salt-forming group is present and reaction in the salt form is possible.
  • the reaction between the compound of formula (V) and the compound of formula (III) takes place in suitable inert polar solvents, especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially, ethanol or n-butanol, or it takes place in a melt without the addition of a solvent, especially when one of the reactants is in liquid form.
  • suitable inert polar solvents especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially, ethanol or n-butanol
  • the reaction takes place at elevated temperatures, preferably from approximately 60° C. to reflux temperature, e.g., under reflux conditions or at a temperature of from approximately 60-110° C.
  • the compound of formula (III) can also be used in the form of a salt, e.g., in the form of an acid addition salt with a strong acid, such as a hydrogen halide, e.g., in the form of the hydrochloride salt; or the corresponding acid, e.g., HCl, can be added in a suitable solvent, e.g., an ether, such as dioxane.
  • a strong acid such as a hydrogen halide, e.g., in the form of the hydrochloride salt
  • a suitable solvent e.g., an ether, such as dioxane.
  • the reaction between the compound of formula (V) and the compound of formula (III) takes place in suitable, inert polar solvents, especially ethers, e.g., THF, or in a melt without the addition of a solvent, especially if one of the reaction partners is present in liquid form.
  • suitable, inert polar solvents especially ethers, e.g., THF
  • the reaction takes place at elevated temperatures, preferably between about 80° C. and 140° C. in a pressure tube.
  • the compound of formula (III) can be used as a salt, e.g., as an basic addition salt with a strong base, such as potassium hydroxide or sodium hydride.
  • Step 2 involves the halogenation, especially bromination of the isoquinolyl nucleus of a compound of formula (VI) in the presence of an electrophilic halogenating agent, preferably phenyltrimethylammonium tribromide in an inert polar solvent, preferably THF at a temperature between 0° C. and the reflux temperature of the solvent, preferably at room temperature for a period of time between 1 hour and 24 hours, preferably for 12 hours to provide a compound of formula (VII).
  • an electrophilic halogenating agent preferably phenyltrimethylammonium tribromide
  • an inert polar solvent preferably THF at a temperature between 0° C. and the reflux temperature of the solvent, preferably at room temperature for a period of time between 1 hour and 24 hours, preferably for 12 hours to provide a compound of formula (VII).
  • Step 3 Involves the preparation of a boronic acid intermediate.
  • the reaction is conducted in the presence of:
  • Step 4 involves the palladium mediated cross-coupling reaction of two suitable coupling partners, preferably under Suzuki conditions.
  • the palladium-mediated coupling is conducted in the presence of:
  • a compound of formula (Ia) can act as an intermediate compound if A, B, E, D or T have a leaving group. In that case, an amine, oxygen or sulfur nucleophile acts to displace the leaving group, resulting in an alternative final compound of formula (Ia).
  • This synthesis involves the reaction between the compound of formula (Ia), wherein Q comprises a reactive group; and a compound of formula (Q-H), where Q is selected from OR 2 , —SR 2 , —NR 2 , —NRS(O) 2 N(R) 2 , —NRS(O) 2 R takes place in suitable, inert polar solvents, especially alcohols, e.g., lower alkanols, such as methanol, propanol or, especially ethanol or n-butanol, or in a melt without the addition of a solvent, especially if one of the reaction partners is present in liquid form.
  • the reaction takes place at elevated temperatures, preferably between about 60° C.
  • the compound of formula (Q) can be used as a salt, e.g., as an acid addition salt with a strong acid, such as hydrogen halide, e.g., as a hydrochloride salt.
  • the reaction between the compound of formula (Ia) and the compound of formula (Q-H), as defined above takes place in suitable, inert polar solvents, especially ethers, e.g., THF, or in a melt without the addition of a solvent, especially if one of the reaction partners is present in liquid form.
  • suitable, inert polar solvents especially ethers, e.g., THF
  • the reaction takes place at elevated temperatures, preferably between about 80° C. and 140° C. in a pressure tube.
  • the compound of formula (III) can be used as a salt, e.g., as an basic addition salt with a strong base, such as potassium hydroxide or sodium hydride.
  • the other starting materials are known, can be prepared by processes known per se, or are available commercially or, in particular, can be prepared by processes analogous to those mentioned in the Examples.
  • the starting material is prepared as follows:
  • the oil is purified by flash chromatography (SiO 2 : hexanes/ethyl acetate). A light yellow oil is collected and crystallized from hexane, m.p. 105-106° C. CHN analysis calc. % C, 61.67; % H, 4.31; % N, 14.98. Found % C, 61.70; % H, 4.64; % N, 14.93.
  • the starting material is prepared as follows:
  • N-oxide (15.75 g, 0.0703 mol) is dissolved in chloroform (50 mL) and cooled in an ice bath.
  • Phosphorus oxychloride (20 mL) is added dropwise and then the mixture is warmed to room temperature and then heated to reflux for 1.5 hours. The mixture is allowed to cool to room temperature and is then poured over ice.
  • the aqueous mixture is neutralized to pH 7-8 with NaHCO 3 and then extracted with chloroform.
  • the organic phase is washed with brine, dried over sodium sulfate and the solvent is removed.
  • 2,4-Dichloropyrimidine (1.54 g, 10.3 mmol) and (4-boronic acid-isoquinolin-1-yl)-(4-tert-butyl-phenyl)-amine (3.00 g, 9.37 mmol) are combined in 45 mL ethylene glycol DME in a large sealed tube.
  • the PdCl 2 (PPh 3 ) 2 catalyst (0.66 g, 0.94 mmol) and a 3.0 M aqueous solution of Na 2 CO 3 (12.5 mL, 37.5 mmol) are added and N 2 is bubbled through the solution for 5 minutes.
  • the reaction mixture is then heated to 85-90° C. for 2.5 hours.
  • N-(4-tert-Butyl-2-fluoro-phenyl)-acetamide (70 mg, 0.33 mmol) is dissolved in EtOH (2 mL) with 1N HCl (10 ml, 0.01 mmol) and heated to reflux for 72 hr. The reaction is cooled to rt and the volatiles removed in vacuo. The remaining aqueous solution is washed 1 ⁇ 5 mL Et 2 O, made basic with sat. NaHCO 3 , and extracted 3 ⁇ 5 mL CH 2 Cl 2 . Organic extracts are combined and dried over Na 2 SO 4 . Volatiles are removed to yield 30 mg (54%) product 4-tert-Butyl-2-fluoro-phenylamine as a straw colored oil.
  • 6-tert-Butyl-pyridin-3-ylamine is coupled to 1-chloro-4-(2-morpholin-4-yl-pyrimidin-4-yl)-isoquinoline as described in Example 2: API-MS, m/z 441.44 ([M+H] + , calcd. 441.23).
  • Zinc dust (3.13 g, 48 mmol) is added in a single portion to a solution of N′-(6-tert-butyl-pyridin-3-yl)-hydrazinium hydrochloride (1.2 g, 6.0 mmol) in methanol (30 mL) and 4M HCl/dioxane (12 mL, 48 mmol) and the solution stirred at rt for two days until the starting material hydrazine is consumed. Volatiles are removed via rotovap and the residue treated with 40 mL 28% aqueous ammonia. The product is then extracted into ether (3 ⁇ 30 mL), shaken with brine, dried over Mg 2 SO 4 and filtered. Volatiles are removed to yield 0.802 g (89%) product as an orange solid; mp 61.5-62.7° C. API-MS, m/z 151.16 ([M+H] + , calcd. 151.11).
  • 6-tert-Butyl-pyridin-3-ylamine is coupled to 1-Chloro-[4,7′]biisoquinolinyl as described in Example 7.
  • a microwave reaction vial is charged with (4-boronic acid-isoquinolin-1-yl)-(4-tert-butylphenyl)-amine (120.9 mg, 0.38 mmol, 1.2 eq), K 2 CO 3 (128.7 mg, 0.93 mmol, 3 eq), 6-bromo-4-morpholin-4-yl-quinazoline (92.5 mg, 0.31 mmol, 1 eq) and 4:1 DME:H 2 O (5 mL). N 2 gas is bubbled through this mixture. PdCl 2 (PPh 3 ) 2 (47.8 mg, 0.068 mmol, 0.22 eq) is added and the vial sealed. This is heated to 120° C. for 30 min under microwave heating.
  • PBr 3 (11 g, 36.9 mmol, 5.5 eq) is added to 2,6-dichloro-pyrazine (1.0 g, 6.7 mmol, 1 eq) at rt and heated to 150° C. for 24 h.
  • This solution is dried in vacuum and the residue is dissolved in CH 2 Cl 2 (50 mL).
  • the organics are washed with H 2 O, brine and dried.
  • Morpholine is added to this solution dropwise at 0° C. and warmed to rt in 5 h.
  • the solution is washed with H 2 O and brine.
  • Trimethylphenylammonium tribromide (1.03 g, 2.74 mmol) is added to a solution of (4-Isopropyl-phenyl)-[2,6]naphthyridin-1-yl-amine (680 mg, 2.58 mmol) in THF (10 mL) at 0° C. The solution is warmed up to rt and stirred for 1 h. THF is evaporated to dryness and the residue is dissolved in CH 2 Cl 2 (20 mL). The solution is washed with H 2 O (1 ⁇ 10 mL) and brine (1 ⁇ 10 mL). The organics are dried (Na 2 SO 4 ) and concentrated to 2 mL.
  • Active B-Raf, C-Raf, and V599E B-Raf proteins of human sequence are purified from insect cells using the baculoviral expression system. Raf inhibition is tested in 96-well microplates coated with I ⁇ B- ⁇ and blocked with Superblock. The phosphorylation of I ⁇ B- ⁇ at Serine 36 is detected using a phospho-I ⁇ B- ⁇ specific antibody (Cell Signaling #9246), an anti-mouse IgG alkaline phosphatase conjugated secondary antibody (Pierce #31320), and an alkaline phosphatase substrate, ATTOPHOS (Promega, #S101).
  • Genomic DNA is isolated from human cells from a melanoma cell line using a GENELUTE mammalian genomic DNA kit (Sigma Cat. # G1N 350). PCR reactions are carried out on a PCR machine (MJ Research, Model PTC100) in a total volume of 50 mL using the PCR Core kit by Roche (Cat. # 1578 553).
  • the PCR reaction mixture contains 5 mL of 10 ⁇ reaction buffer, 1 mL of 10 mM dNTPs, 100-1000 ng of template DNA, 0.5 mL Taq polymerase (2.5-5 units), 1 mL of a 31 ⁇ M stock of each primer.
  • the PCR conditions are as follows:
  • the faster migrating band runs ahead of the 100 bp marker and represents the primers.
  • the DNA that results from the T1796A mutant specific PCR amplification has a predicted size of 152 bp and migrates between the 100 bp standard the 200 bp standard as predicted.
  • the PCR amplification product is confirmed by sequencing. The presence of the PCR amplification product demonstrates that the T1796A mutation is present in the template DNA. The absence of the PCR amplification product is evidence that the mutation is absent in the tissue sample.

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